scholarly journals Biochemical characterization of P-type copper ATPases

2014 ◽  
Vol 463 (2) ◽  
pp. 167-176 ◽  
Author(s):  
Giuseppe Inesi ◽  
Rajendra Pilankatta ◽  
Francesco Tadini-Buoninsegni
Keyword(s):  
Metal Binding ◽  
Binding Sites ◽  
Mammalian Cells ◽  
Plasma Membranes ◽  
Transition Metal Ions ◽  
Cation Binding ◽  
Cancer Drug ◽  
Catalytic Activation ◽  
Copper Atpases ◽  
Metal Binding Domain

Copper ATPases, in analogy with other members of the P-ATPase superfamily, contain a catalytic headpiece including an aspartate residue reacting with ATP to form a phosphoenzyme intermediate, and transmembrane helices containing cation-binding sites [TMBS (transmembrane metal-binding sites)] for catalytic activation and cation translocation. Following phosphoenzyme formation by utilization of ATP, bound copper undergoes displacement from the TMBS to the lumenal membrane surface, with no H+ exchange. Although PII-type ATPases sustain active transport of alkali/alkali-earth ions (i.e. Na+, Ca2+) against electrochemical gradients across defined membranes, PIB-type ATPases transfer transition metal ions (i.e. Cu+) from delivery to acceptor proteins and, prominently in mammalian cells, undergo trafficking from/to various membrane compartments. A specific component of copper ATPases is the NMBD (N-terminal metal-binding domain), containing up to six copper-binding sites in mammalian (ATP7A and ATP7B) enzymes. Copper occupancy of NMBD sites and interaction with the ATPase headpiece are required for catalytic activation. Furthermore, in the presence of copper, the NMBD allows interaction with protein kinase D, yielding phosphorylation of serine residues, ATP7B trafficking and protection from proteasome degradation. A specific feature of ATP7A is glycosylation and stabilization on plasma membranes. Cisplatin, a platinum-containing anti-cancer drug, binds to copper sites of ATP7A and ATP7B, and undergoes vectorial displacement in analogy with copper.

MVP interacts with YPEL4 and inhibits YPEL4-mediated activities of the ERK signal pathway

2010 ◽  
Vol 88 (3) ◽  
pp. 445-450 ◽  
Author(s):  
Pei Liang ◽  
Yongqi Wan ◽  
Yan Yan ◽  
Yuequn Wang ◽  
Na Luo ◽  
...  
Keyword(s):  
Metal Binding ◽  
Mammalian Cells ◽  
Mapk Signaling ◽  
Reporter System ◽  
Biochemical Assays ◽  
Metal Binding Domain ◽  
Erk Signal Pathway ◽  
Gene Maps ◽  
Putative Zinc Finger ◽  
Two Hybrid

Human YPEL4 is a member of YPEL family. It contains a Yippee domain, which is a putative zinc-finger-like, metal-binding domain. The human YPEL4 gene maps to chromosome 11q12.1, is ubiquitously expressed in adult tissues, and encodes a nuclear protein of 127 amino acids, the function of which remains unknown. To gain insights into the cellular function of this protein, we searched for YPEL4-interacting proteins using a yeast two-hybrid screen. The major vault protein (MVP), a lung resistance associated protein, was identified as a binding partner of YPEL4. The interaction between YPEL4 and MVP in mammalian cells was further demonstrated by a series of biochemical assays including the mammalian two-hybrid assay, GST pull-down assay, co-immunoprecipitation assay, and immunocytochemistry. Using a reporter system, we found that MVP can inhibit YPEL4’s ability to activate Elk-1 in the MAPK signaling pathway. This study provides new clues for understanding the molecular mechanism of YPEL4 in cell division and signal transduction pathways and should be helpful for understanding molecular functions of the YPEL family.

scholarly journals The soluble metal-binding domain of the copper transporter ATP7B binds and detoxifies cisplatin

2009 ◽  
Vol 419 (1) ◽  
pp. 51-59 ◽  
Author(s):  
Nataliya V. Dolgova ◽  
Doug Olson ◽  
Svetlana Lutsenko ◽  
Oleg Y. Dmitriev
Keyword(s):  
Metal Binding ◽  
Binding Sites ◽  
Active Drug ◽  
Binding Domain ◽  
Copper Binding ◽  
Protein Fragment ◽  
Copper Transporter ◽  
Metal Binding Domain ◽  
Cell Expression

Wilson disease ATPase (ATP7B) has been implicated in the resistance of cancer cells to cisplatin. Using a simple in vivo assay in bacterial culture, in the present study we demonstrate that ATP7B can confer resistance to cisplatin by sequestering the drug in its N-terminal metal-binding domain without active drug extrusion from the cell. Expression of a protein fragment containing four N-terminal MBRs (metal-binding repeats) of ATP7B (MBR1–4) protects cells from the toxic effects of cisplatin. One MBR1–4 molecule binds up to three cisplatin molecules at the copper-binding sites in the MBRs. The findings of the present study suggest that suppressing enzymatic activity of ATP7B may not be an effective way of combating cisplatin resistance. Rather, the efforts should be directed at preventing cisplatin binding to the protein.

scholarly journals Sugar Transport and Metal Binding in Yeast

1965 ◽  
Vol 49 (2) ◽  
pp. 235-246 ◽  
Author(s):  
Johnny van Steveninck ◽  
Aser Rothstein
Keyword(s):  
Metal Binding ◽  
Binding Sites ◽  
Equilibrium Distribution ◽  
Sugar Transport ◽  
Cation Binding ◽  
Facilitated Diffusion ◽  
Low Concentrations ◽  
Michaelis Constants ◽  
High Concentrations ◽  
Phosphoryl Groups

The uptake of sugars by yeast can be separated into two classes. The first involves the uptake of sorbose or galactose by starved cells, and the uptake of glucose by iodoacetate-poisoned cells. These uptakes do not involve any changes in Ni++- or Co++-binding by the cell surface, are not inhibited by Ni++, are inhibited by UO2++ in relatively high concentrations, are characterized by high Michaelis constants and low maximal rates and by a final equilibrium distribution of the sugars. The second involves the uptake of glucose in unpoisoned cells and galactose in induced cells. These uptakes are characterized by a reduction of Ni++- and Co++-binding, by a partial inhibition by Ni++, by an inhibition with UO2++ in relatively low concentrations, and by a low Km and a high Vm. In the case of galactose in induced cells, previous studies demonstrate that the sugar is accumulated against a concentration gradient. It is suggested that the first class of uptakes involves a "facilitated diffusion" via a relatively non-specific carrier system, but the second represents an "uphill" transport involving the highly specific carriers, and phosphoryl groups (cation-binding sites) of the outer surface of the cell membrane.

Inhibitor Binding Sites in the Protein Tyrosine Phosphatase SHP-2

2020 ◽  
Vol 20 (11) ◽  
pp. 1017-1030
Author(s):  
Haonan Zhang ◽  
Zhengquan Gao ◽  
Chunxiao Meng ◽  
Xiangqian Li ◽  
Dayong Shi
Keyword(s):  
Small Molecule ◽  
Protein Tyrosine Phosphatase ◽  
Binding Sites ◽  
Drug Target ◽  
Tyrosine Phosphatase ◽  
Cancer Drug ◽  
Cellular Activity ◽  
Binding Modes ◽  
Inhibitor Binding ◽  
Protein Tyrosine

Protein tyrosine phosphatase 2 (SHP-2) has long been proposed as a cancer drug target. Several small-molecule compounds with different mechanisms of SHP-2 inhibition have been reported, but none are commercially available. Pool selectivity over protein tyrosine phosphatase 1 (SHP-1) and a lack of cellular activity have hindered the development of selective SHP-2 inhibitors. In this review, we describe the binding modes of existing inhibitors and SHP-2 binding sites, summarize the characteristics of the sites involved in selectivity, and identify the suitable groups for interaction with the binding sites.

scholarly journals Metal Binding Proteins

Encyclopedia ◽  
2021 ◽  
Vol 1 (1) ◽  
pp. 261-292
Author(s):  
Eugene A. Permyakov
Keyword(s):  
Metal Ions ◽  
Metal Binding ◽  
Transition Metal Ions ◽  
Short Review ◽  
Sodium Potassium ◽  
Physical Chemical ◽  
Physiological Properties ◽  
Cell Processes ◽  
Living Organisms ◽  
Potassium Magnesium

Metal ions play several major roles in proteins: structural, regulatory, and enzymatic. The binding of some metal ions increase stability of proteins or protein domains. Some metal ions can regulate various cell processes being first, second, or third messengers. Some metal ions, especially transition metal ions, take part in catalysis in many enzymes. From ten to twelve metals are vitally important for activity of living organisms: sodium, potassium, magnesium, calcium, manganese, iron, cobalt, zinc, nickel, vanadium, molybdenum, and tungsten. This short review is devoted to structural, physical, chemical, and physiological properties of proteins, which specifically bind these metal cations.

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